Molecules with extended half-lives, compositions and uses thereof

Abstract

The present invention provides molecules, including IgGs, non-IgG immunoglobulin, proteins and non-protein agents, that have increased in vivo half-lives due to the presence of an IgG constant domain, or a portion thereof that binds the FcRn, having one or more amino acid modifications that increase the affinity of the constant domain or fragment for FcRn. Such proteins and molecules with increased half-lives have the advantage that smaller amounts and or less frequent dosing is required in the therapeutic, prophylactic or diagnostic use of such molecules.

Description

[0001]This application claims the benefit of U.S. provisional application Ser. Nos. 60 / 254,884, filed Dec. 12, 2000, and 60 / 289,760, filed May 9, 2001, both of which are incorporated by reference herein in their entireties.[0002]This invention was made, in part, with United States Government support under award number A139167 from the National Institute of Health. The United States Government may have certain rights in the invention.1. INTRODUCTION[0003]The present invention relates to molecules whose in vivo half-lives are increased by modification of an IgG constant domain, or FcRn (Fc Receptor-neonate) binding domain thereof. Specifically, these molecules have amino acid modifications that increase the affinity of the constant domain or fragment thereof for the FcRn. Increasing the half-life of therapeutic and diagnostic IgGs and other bioactive molecules using methods of the invention has many benefits including reducing the amount and / or frequency of dosing of these molecules, ...

AI Technical Summary

Benefits of technology

The present invention is based on the discovery of mutations in the constant domain of human IgG molecules that increase their affinity for the FcRn receptor, which results in a longer half-life for the molecule in the body. These mutations can be introduced into the constant domain of an IgG molecule to create a modified molecule with increased half-life. The invention also includes a method for identifying these mutations through screening libraries of human IgG molecules. The invention can be applied to create bioactive molecules with increased half-life, such as immunoglobulins, by incorporating an IgG constant domain with modified amino acid residues that increase its affinity for FcRn.

Problems solved by technology

One critical issue in these therapies is the persistence of immunoglobulins in the circulation.

Increased dosage and frequency of dosage may cause adverse effects in the patient and also increase medical costs.

However, none of these publications disclose specific mutants in the IgG constant domain that affect half-life.

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